Document Detail


A novel MEK1/2 inhibitor induces G1/S cell cycle arrest in human fibrosarcoma cells.
MedLine Citation:
PMID:  20596617     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Blockade of the ERK pathway has antitumor effects against malignant tumor cells. In this study, we investigated the antitumor activity of JTP-70902, a novel specific MEK inhibitor, against human fibrosarcoma cells in which the ERK pathway is constitutively activated. JTP-70902 was synthesized at Japan Tabacco. Human fibrosarcoma HT1080 cells were cultured. JTP-70902 was added at various concentrations. The number of viable cells was counted employing a trypan blue dye exclusion test. Unsynchronized cells were exposed to JTP-70902 for 24 h. The nuclei were stained with propidium iodide. The DNA content was measured using a FACSCalibur flow cytometer. Protein extraction and Western blot analysis were performed. (1) A dose-dependent inhibition of cell growth was observed at concentrations of 10 nM or more. Forty-eight hours after the treatment, the growth of HT1080 cells was completely inhibited by 200 nM JTP-70902. (2) FACS analysis revealed that a 24-h exposure to JTP-70902 increased the population of G1/S phase cells in a dose-dependent manner. (3) The phosphorylation of ERK was inhibited by JTP-70902. Furthermore, after the treatment with JTP-70902, p21WAF1/CIP1 and p27KIP1 protein expression increased and the phosphorylation of RB was reduced. Our results showed that JTP-70902 inhibits cell growth and induces cell cycle arrest in human Ras mutant fibrosarcoma cells. These results indicate that JTP-70902 might be an attractive compound for molecular-targeting chemotherapy for malignant soft tissue tumors with the activation of the Ras-MEK-ERK pathway.
Authors:
Taka-Aki Matsui; Hiroaki Murata; Yoshihiro Sowa; Tomoya Sakabe; Kazutaka Koto; Naoyuki Horie; Yoshiro Tsuji; Toshiyuki Sakai; Toshikazu Kubo
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Oncology reports     Volume:  24     ISSN:  1791-2431     ISO Abbreviation:  Oncol. Rep.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-07-02     Completed Date:  2010-11-10     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9422756     Medline TA:  Oncol Rep     Country:  Greece    
Other Details:
Languages:  eng     Pagination:  329-33     Citation Subset:  IM    
Affiliation:
Department of Orthopaedics, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 602-8566, Japan.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Cell Cycle / drug effects*,  physiology
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
Cyclin-Dependent Kinase Inhibitor p27 / metabolism
Drug Evaluation, Preclinical
Fibrosarcoma / pathology*
G1 Phase / drug effects
Humans
MAP Kinase Kinase 1 / antagonists & inhibitors*
MAP Kinase Kinase 2 / antagonists & inhibitors*
Protein Kinase Inhibitors / pharmacology*
Pyrimidinones / pharmacology
S Phase / drug effects
Sulfonamides / pharmacology
Time Factors
Tumor Cells, Cultured
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/CDKN1A protein, human; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/N-(3-(5-(4-bromo-2-fluorophenylamino)-3-cyclopropyl-8-methyl-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido(2,3-d)pyrimidin-1-yl)phenyl)methanesulfonamide; 0/Protein Kinase Inhibitors; 0/Pyrimidinones; 0/Sulfonamides; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; EC 2.7.1.-/MAP2K1 protein, human; EC 2.7.1.-/MAP2K2 protein, human; EC 2.7.12.2/MAP Kinase Kinase 1; EC 2.7.12.2/MAP Kinase Kinase 2

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